Population Genetics and Multifactorial Inheritance 2002

1
Population GeneticsandMultifactorial
Inheritance 2002

• Consanguinity
• Genetic drift
• Founder effect
• Selection
• Mutation rate
• Polymorphism
• Balanced polymorphism

• Hardy-Weinberg Equilibrium

2
Hardy-Weinberg Equilibrium

• Explains why, In a large population with random
  mating
• 1. Allele frequencies do not change from
  generation to generation
• 2. Genotype frequencies are determined by allele
  frequencies at that locus

3
(No Transcript)
4
(No Transcript)
5
Note error in AA offspring footer !
6
(No Transcript)
7
Allele frequencies in X-linked disorders

• Males are hemizygous for the X-chromosome
  therefore frequency of affected males frequency
  of the mutant allele, q
• For rare XLR disorders, frequency of heterozygous
  carrier females is twice the frequency of
  affected males, or 2q
• Frequency of homozygous females is very low, q²

8
Applications of HWE

• Determination of allele frequency and
  heterozygote carrier frequency in a population
  for which the frequency of the trait is known

9
Hemophilia A and Para-hemophilia

• Hemophilia A
• XLR
• Frequency 1/5000
• Female carriers 1/2500
• Parahemophilia
• Rare AR
• Frequency 1/1,000,000
• Heterozygote carrier frequency 1/500

10
Factors that alter gene frequency

• Small populations/ Non-random mating
• Selection
• Mutation
• Migration and gene flow

11
Coefficient of relationship

• Parent-child First ½
• Siblings First ½
• Uncle-niece Second ¼
• First cousins Third 1/8

12
Selected Michigan Marriage Laws(Amended 1956)

• SEC 3. No man shall marry his mother,
  grandmother, daughter, granddaughter, stepmother,
  grandfathers wife, sons wife, grandsons
  wife..or cousin of the first degree.

13
Genetic Drift/ Founder EffectSingle (few)
founder mutations

• Finns (located on the edge of the populated
  world)
• Indo-European immigration 2000 years ago
• Population of 50,000 in 12th century, 5 million
  today
• Ashkenazim
• Migration to Rhineland in 9th century, to Eastern
  Europe in 14th century
• Population 10-20,000 in Poland in 16th century,
  11M worldwide today
• Repeated bottlenecks (pogroms)
• Amish

14
(No Transcript)
15
Factors that alter gene frequency

• Small populations/ Non-random mating
• Selection
• Mutation
• Migration and gene flow

16
Selection

• Biological fitness (f)
• Positive and negative selection
• Selection on AD, AR, XLR

17
Factors that alter gene frequency

• Small populations/ Non-random mating
• Selection
• Mutation
• Migration and gene flow

18
Mutation

• Effect of gene size
• Effect of paternal age
• Balance between introduction of new mutant
  alleles by mutation and removal by negative
  selection

19
Factors that alter gene frequency

• Small populations/ Non-random mating
• Selection
• Mutation
• Migration and gene flow

20
Migration and gene flow

• Tracking human migrations
• Cohanim
• Lemba

21
Polymorphism

• The occurrence of two or more genetically
  determined alternative phenotypes in a population
  at such a frequency that the rarest could not be
  maintained by recurrent mutation alone
• Practically---a genetic locus is considered
  polymorphic if one or more of the rare alleles
  has(have) a frequency of at least 0.01.
• Examples MHC, SNPs, SSRs

22
Balanced polymorphism

• Balance of positive and negative selection

Malaria and genetic disorders of red blood cells
23
Multifactorial Inheritance

• Complex Common Diseases

24
(No Transcript)
25
Evidence for Genetic Factors in Common Complex
Diseases

• Familial aggregation
• Twin studies
• Mendelian forms of disease

26
Familial Aggregation
27
Increased risk to relatives ?R

• ?S
• IDDM 10-15
• NIDDM 4
• ?1
• Schizophrenia 10
• Autism 100

28
MD (and MD2B) A chronic condition with
significant physical, mental, emotional, and
financial consequences

• A a first degree relative (sib,parent)
• B a second degree relative (aunt,uncle,
  grandparent
• C More than one 1st and/or 2nd degree relative
• D No affected 1st or 2nd degree relatives

29
Evidence for Genetic Factors in Common Complex
Diseases

• Familial aggregation
• Twin studies
• Mendelian forms of disease

30
Twin Studies
31
Twin studies in infectious disease
MZ DZ

• Tuberculosis (USA)
• Leprosy (India)
• Poliomyelitis (USA)
• Hepatitis B (Taiwan)

• 62 18
• 52 22
• 36 6
• 35 4

32
Evidence for Genetic Factors in Common Complex
Diseases

• Familial aggregation
• Twin studies
• Mendelian forms of disease

33
Diabetes Mellitus

• Maturity onset diabetes of the young (MODY)

34
Association and Linkage

• ASSOCIATION of a specific allele at a genetic
  locus with disease in a population
• Candidate gene
• LINKAGE. Co-segregation in families of a marker
  locus, regardless of specific allele, with
  disease.

35
Implications

• Identification of genetic markers of liability to
  common complex disease.
• Environmental triggers have greatest impact on
  genetically predisposed.
• Identification of susceptible individuals aids
  identification of environmental triggers.
• Medical intervention can be focused on those at
  greatest risk.

36
Threshold Model
37
(No Transcript)
38
Predictions from Threshold Model

• Recurrence risks are average
• Risk increases with of affected relatives
• Risk increases with severity of malformation
• Differential risk increases as frequency
  decreases
• Sex differences

39
(No Transcript)
40
(No Transcript)
41
Affected Sib Pair